The R enantiomer of .alpha.-liponic acid is a natural product, which occurs in small concentrations in practically all animal and plant cells. .alpha.-Liponic acid is of vital importance as a coenzyme of the oxidative decarboxylation of .alpha.-ketocarboxylic acids, such as pyroracemic acid. The racemate of .alpha.-liponic acid is pharmacologically active and has antiphlogistic and antinociceptive (analgesic) as well as cyto-protective properties. An important medicinal indication is the treatment of diabetic polyneuropathy. According to more recent results, as published, for example in CA 116: 207360, .alpha.-liponic acid can be of importance as a remedy for diseases caused by HIV-1 and HTLV IIIB viruses.
In the case of the pure optical isomers of .alpha.-liponic acid, the R and S forms, that is, R-.alpha.-liponic acid and S-.alpha.-liponic acid, the R enantiomer, contrary to the racemate, predominantly has antiphlogistic activity and the S enantiomer predominantly has antinociceptive activity as detailed in European patent No. 427,2447, of Nov. 8, 1990. For this reason, the synthesis of the pure enantiomers is of great importance.
Known methods for synthesizing enantiomerically pure .alpha.-liponic acid comprise splitting the racemate of .alpha.-liponic acid or its intermediates, asymmetric syntheses using chiral auxiliaries, so called "chiral pool" syntheses involving the use of naturally occurring, optically active starting compounds, as well as microbial syntheses, as referred to in survey articles of J. S. Yadav et al., J. Sci. Ind. Res. 1990, 49, 400; E. Walton et al., J. Am. Chem. Soc. 1955, 77, 5144; D. S. Acker and W. J. Wayne, J. Am. Chem. Soc. 1957, 79 6483; L. G. Chebotareva and A. M. Yurkevich, Khim.-Farm. Zh. 1980, 14, 92, A. G.; Tolstikov et al., Bioorg. Khim. 1990, 16, 1670; L. Dasaradhi et al., J. Chem. Soc., Chem. Commun. 1990, 729; A. S. Gopalan et al., J. Chem. Perkin Trans. 1 1990, 1897; A. S Gopalan et al., Tetrahedron Letters 1989, 5705; and in European patent No. 487,986 A2, 14, of Nov. 14, 1991).
Racemate splitting by forming diastereoisomeric salts of .alpha.-liponic acid with optically active .alpha.-methylbenzylamine, as described in German published patent application No. 44137773.7, of Nov, 16, 1991, represents the most economic variation so far. However, the disadvantage of this method is that the separation of the racemate takes place only in the last step of the synthesis sequence and that the undesirable enantiomers of a-liponic acid can neither be racemized nor inverted. In other known methods of splitting the racemic intermediate of .alpha.-liponic acid, in each case only one enantiomer can be converted into the desired optical isomer of .alpha.-liponic acid. Accordingly, only a theoretical yield of 50% can be attained as described by E. Walton et al., J. Am. Chem. Soc. 1955, 77; 5144, D. S. Acker and W. J. Wayne, J. Am. Chem. Soc. 1957, 79, 6483; and L. G. Chebotareva and A. M. Yurkevich, Khim.-Farm. Zh. 1980, 14, 92).